The invention relates to aminomethylcarboxylic acid derivatives, to pharmaceutical compositions containing the same, as well as to the use of these aminomethylcarboxylic acid derivatives in therapy.
The simplest xcex1-amino acid glycine, or aminomethylcarboxylic acid, has a number of important roles in the mammalian central nervous system (CNS). Along with xcex3-aminobutyric acid (GABA), it is a major post-synaptic inhibitory transmitter in the spinal cord and brainstem, acting through ligand gated ion channels. Interaction of glycine with these receptors can be antagonized by the alkaloid strychnine. These receptors are therefore referred to as xe2x80x98strychnine sensitivexe2x80x99 glycine receptors. Glycinergic neurotransmission is important in the processing and control of visual, auditory and motor signalling. Glycine is also an obligatory co-agonist along with glutamate at the N-methyl-D-aspartate (NMDA) receptor. Glycine therefore functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the CNS. In addition the amino acid plays a role in the metabolism of peptides and proteins, including the exchange of one-carbon units.
Control of the availability of glycine for any of the above processes will potentially influence their function and provide means of treating a number of diseases and conditions. Apart from metabolism, one of the major processes controlling the concentrations of free glycine in the proximity of strychnine-sensitive and strychnine-insensitive glycine receptors is the functioning of selective high affinity glycine transporters. These proteins can actively limit the spread of glycine beyond the immediate environs of receptors, thus maintaining both spatial and temporal fidelity of receptor activation. Rapid sequestering of transmitter into neuronal or glial cells via the transporter will also conserve glycine for future release.
Glycine transporters have been cloned to reveal two major classes, GlyT-1 and GlyT-2. GlyT-1 is expressed throughout the brain with higher mRNA levels being detected in caudal areas and cellular localisation being predominantly glial. Three isoforms of GlyT-1, 1a, 1b and 1c, arising from differential splicing and exon usage have been identified by Kim et al. (Molecular Pharm. 1994, 45, 608-617).
GlyT-2 distribution, as indicated by immunochemistry studies, corresponds closely to that of inhibitory xe2x80x98strychnine sensitivexe2x80x99 glycine receptors, particularly in the spinal cord.
By regulating the synaptic levels of glycine, the glycine transporters GlyT-1 and GlyT-2 are expected to selectively influence the activity at NMDA receptors and at strychnine-sensitive glycine receptors, respectively.
Compounds which after the functional activity of glycine transporters may therefore result in changes in tissue glycine levels which can be useful in the treatment of a number of disease states. Such disease states include those associated with decreased or exaggerated function of NMDA receptors, namely psychosis, depression, dementia and other forms of impaired cognition, such as attention deficit disorders. NMDA receptors have further been implicated in conditions arising from neuronal cell death and neurodegeneration such as, for example, stroke (head trauma), Alzheimer""s disease, Parkinson""s disease and Huntington""s disease. Enhanced inhibitory glycinergic transmission resulting from inhibition of GlyT-2 or GlyT-1 activity may be useful in the treatment of muscle hyperactivity associated with spasticity, myoclonus and epilepsy. Compounds elevating spinal glycine may also possess analgesic properties.
Aminomethylcarboxylic acid derivatives, wherein the amino group carries an ethyl or a propyl-group which is substituted by two or three aryl and/or aryloxy groups, are disclosed in WO 97/45115 (TROPHIX PHARM. INC.) as compounds useful in the treatment of the neurological and neuropsychiatric disorders discussed above. Structurally related aminomethylcarboxylic acid derivatives, wherein the aminogroup is part of a cyclic amine which is substituted at a single position with (a substituent containing) two aryl or cycloalkyl groups, are disclosed in WO 97/45423 (TROPHIX PHARM. INC.) as having similar activity.
There exists a need for additional compounds suitable for the treatment of psychiatric and neurological disorders, especially for compounds having a selective pharmacological profile.
To that aim the present invention provides in a first aspect aminomethylcarboxylic acid derivatives having the general formula I 
wherein
Z is (CH2)n, O, S, SO, SO2 or Nxe2x80x94R5;
n is 0, 1 or 2;
X represents 1-3 substituents independently selected from hydrogen, halogen, (C1-6)alkyloxy, (C3-6)cycloalkyloxy, (C6-12)aryloxy, (C6-12)aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NHSO2R6, CN, COOR6 and (C1-4)alkyl, optionally substituted with halogen, (C6-12)aryl, (C1-6)alkyloxy or (C6-12)aryloxy; or 2 substituents at adjacent positions together represent a fused (C5-6)aryl group, a fused (C5-6)cycloalkyl ring or Oxe2x80x94(CH2)mxe2x80x94O; m is 1 or 2;
Y represents 1-3 substituents independently selected from hydrogen, halogen, (C1-4)alkyloxy, SR6, NR6R6 and (C1-4)alkyl, optionally substituted with halogen;
R1 is COOR7 or CONR8R9;
R2 and R6 are (C1-4)alkyl;
R3, R4 and R5 are independently hydrogen or (C1-4)alkyl;
R7, R8 and R9 are independently hydrogen, (C1-4)alkyl, (C6-12)aryl or arylalkyl;
or a pharmaceutically acceptable salt thereof.
The term (C1-4)alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having 1-4 carbon atoms, for example, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
In the term (C1-6)alkyloxy, (C1-6)alkyl means a branched or an unbranched alkyl group having 1-6carbon atoms, for example hexyl, pentyl, neopentyl (2,2-dimethylpropyl) and the meanings given above for (C1-4)alkyl. The (C1-6)alkyloxy group may be substituted with halogen, (C3-6)cycloalkyl or (C1-4)alkyloxy. Examples of such substituted (C1-6)alkyloxy groups are trifluoromethyloxy and cyclopropylmethyloxy.
The term (C3-6)cycloalkyl means a cyclic alkyl group having 3-6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term halogen means F, Cl, Br, or I. When halogen is a substituent at an alkyl group, F is preferred. A preferred halogen substituted alkyl group is trifluoromethyl.
In the term (C6-12)aryloxy, as used in the definition of formula I, (C6-12)aryl means an aromatic group having 6-12 carbon atoms for example phenyl, naphthyl or biphenyl. These aromatic groups may be substituted with halogen, or with (C1-4)alkyl or (C1-4)alkyloxy, wherein (C1-4)alkyl has the previously given meaning and may be substituted with halogen or (C1-4)alkyloxy.
The term arylalkyl, as used in the definition of Formula I, means a (C1-4)alkyl group which is substituted with a (C6-12)aryl group, for example, benzyl.
In the definition of formula I, X can represent a fused (C5-6)aryl group, which means that X is a 5 or 6-membered aromatic ring fused to the benzene ring to which X is attached to form a (C11-12)aromatic ring system, for example a naphthalene or an indene ring. X can also represent a fused (C5-6)cycloalkyl ring, which means that X is a 5- or 6-membered saturated ring fused to the benzene ring to which X is attached to form a tetrahydronaphthalene or an indan ring system. X may further represent Oxe2x80x94(CH2)mxe2x80x94O, wherein m is 1 or 2, which is fused to the benzene ring to which X is attached to form a 1,3-benzodioxole (m=1) or a 1,4-benzodioxan (m=2) ring system.
The meaning of R1 in formula I is exemplified by the groups COOR7 and CONR8R9. In addition R1 may be any other group from which the free acid (R1=COOH) can be generated (in vivo). Such alternative acid precursors or prodrugs, such as further ester or amide derivatives, are known in the art, and are within the scope of the present invention.
The invention includes as specific examples of aminomethylcarboxylic acid derivatives of formula I the (4-phenyl-3,4-dihydro-2H-1-benzothiopyran-3-ylmethyl) aminomethylcarboxylic acid derivatives, wherein Z=S; and the (4-phenyl-3,4-dihydro-2H-1-benzopyran-3-ylmethyl) aminomethylcarboxylic acid derivatives, wherein Z=O.
Preferred aminomethylcarboxylic acid derivatives of the invention correspond to compounds of formula I wherein Z is (CH2)n and n is 1, and wherein R1-R4, X and Y have the previously given meanings. These compounds are (1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) aminomethylcarboxylic acid derivatives, of which the derivatives wherein R2 is methyl and R3 and R4 are hydrogen, are further preferred. Particularly preferred are the derivatives wherein in addition R1 is COOR7. Most preferred are the compounds of formula 1 wherein Z is (CH2)n, n is 1, R1 is COOH, R2 is methyl, R3 and R4 are hydrogen, and pharmaceutically acceptable salts thereof. Ring substituent(s) X, when present, may be in any one and in up to three of the available positions. Specific examples of single ring substituents X includes 6-methoxy, 6-ethoxy, 6-isopropyloxy, 6-phenoxy, 6-cyclohexyloxy, 6-cyano, 6-carboxylate, 6-trifluoromethyl, 6-trifluoromethoxy, 5-fluoro, 7-fluoro and 6-methyl. Substituent Y at the phenyl ring, when present, may be in any one and in up to three of the available positions. Specific examples of single phenyl substituents Y include 3-fluoro and 4-fluoro. An example of multiple substituents include 3,4-difluoro.
The compounds of formula I and their salts contain at least two centres of chirality, i.e. at the two adjacent positions of the Z-containing saturated ring where the phenyl group and the CHR4xe2x80x94NR2xe2x80x94CHR3R1 group are attached, and exist therefore as stereoisomers.
The present invention includes the aforementioned stereoisomers within its scope and each of the individual cis and trans isomers, enantiomers and diastereomers of the compounds of formula I and their salts, substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, and mixtures of such stereoisomers in any proportions including the racemic mixtures containing substantially equal amounts of the two enantiomers.
Preferred are the aminomethylcarboxylic acid derivatives of formula I wherein the phenyl group and the CHR4xe2x80x94NR2xe2x80x94CHR3R1 group occur in the cis-configuration.
The compounds of the invention can be used in the treatment of schizophrenia, depression, dementia and other forms of impaired cognition, for the treatment or prevention of neurodegeneration following stroke or head trauma, for the treatment of neurodegenerative diseases like Alzheimer""s-, Parkinson""s- and Huntington""s disease, for the treatment of muscle hyperactivity associated with spasticity, myoclonus and epilepsy, for the treatment of prevention of pain, mood disorders or learning disorders.
The invention provides in a further aspect pharmaceutical compositions comprising an aminomethylcarboxylic acid derivative having general formula I, of a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries.

Compounds of general formula (I) may be prepared by the reaction of a compound of formula (II) wherein X, Y, Z, R2 and R4 have the previously defined meanings, with a compound of formula Lxe2x80x94CHR1R3, wherein R1 is COOR7 or CONR8R9, R7-R9 and R3 are as defined previously, and L is a suitable leaving group, such as for example halogen, preferably bromo. The reaction is typically carried out in the presence of a suitable solvent such as N,N-dimethylformamide and an acid scavenger such as potassium or cesium carbonate at elevated temperatures, for example at 80xc2x0 C. Compounds of formula (I) wherein R1 is carboxylate COOR7 wherein R7 is hydrogen, may be conveniently prepared by hydrolysis of the corresponding esters COOR7, wherein R7 is (C1-4)alkyl, (C6-12)aryl or arylalkyl, using standard conditions for ester hydrolysis, for example, by heating the aforementioned esters in a mixture of aqueous potassium hydroxide in ethanol at reflux temperature, or by catalytic hydrogenation of, for example, benzyl esters. Compounds of formula (I), wherein R1 is carboxamide CONR8R9, wherein R8 and R9 are (C1-4)alkyl may also be prepared by reaction of the aforementioned carboxylic acids with amines HNR8R9 using standard conditions for amide formation, for example, by reaction of the carboxylic acid with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of a tertiary amine in N,N-dimethylformamide. Alternatively they can be made by, for example by the reaction of the aforementioned carboxylic acids with thionyl chloride or oxalylchloride in methylene chloride containing a catalytic amount of N,N-dimethylformamide followed by reaction of the resulting acid chlorides with amines HNR8R9 in the presence of a tertiary amine acid scavenger in methylene chloride at room temperature.
Compounds of formula (II) wherein the phenyl group and the CHR4xe2x80x94NHR2 group occur in the trans configuration can be prepared from the appropriately substituted 1-phenyl-1,2,3,4-tetrahydro-2-naphthoic acids by methods well known in the art. The aforementioned 1-phenyl-1,2,3,4-tetrahydro-2-naphthoic acids, prepared by the method described in J.Chem.Soc., 1936, 596-599, can, for example, react to form the corresponding acyl halides or anhydrides using standard methods. These in turn, upon reaction with amines R2NH2 followed by reduction of the resulting amides provide the desired compounds (II). For the reduction of the amides, sodium borohydride in the presence of certain catalysts, borane, or lithium aluminium hydride in a non-protic solvent such as diethyl-ether or tetrahydrofuran can be used.
Compounds of formula (II) wherein the phenyl group and the CHR4xe2x80x94NHR2 group occur in the cis configuration are obtained by reaction of compounds of formula (III) with hydrogen in the presence of a palladium on carbon catalyst in ethanol containing aqueous hydrochloric acid. Typically the reaction occurs in the temperature range 0-50xc2x0 C. and at a pressure ranging from 1 to 4 atmospheres. Alternatively, debenzylation can be achieved by treating compounds of formula (III) with (1-chloroethyl)chloroformate in dichloromethane at reflux temperature followed by heating in the presence of methyl alcohol. 
Compounds of formula (III) may conveniently be prepared by dehydration of a compound of formula (IV) using standard conditions, for example using trifluoroacetic acid at room temperature. 
Compounds of formula (IV) may be prepared by reaction of an appropriate aryl organometallic reagent, such as a Grignard or lithium reagent derived from Aryl-L, wherein Aryl represents a phenyl group substituted with Y, which has the meaning as previously defined, and wherein L is a halogen atom such as bromo or chloro, with compounds of formula (V). The reaction is typically carried out in the presence of an apolar, aprotic solvent such as for example diethyl ether at a temperature in the range xe2x88x9210 to +20xc2x0 C. 
Compounds of formula (V) are obtained by reaction of compounds of formula (VI) with the appropriate aldehyde HCOxe2x80x94R4 and a compound of formula NHR2CH2C6H5 in ethanol containing aqueous hydrochloric acid at reflux. 
Compounds of formula (VI) are commercially available or are prepared by methods described in the literature. Such methods are, for example, described in Comprehensive Organic Transformations (by Richard C. Larock, 1989, VCH). For example, the compound of formula VI wherein X is 6-fluoro and Z is methylene may be prepared by cyclisation of 4-(3-fluorophenyl)butyric acid using an acid catalyst such as polyphosphoric acid. The latter compound can be conveniently prepared by reaction of 3-fluorobenzaldehyde with methyl acrylate in the presence of potassium cyanide in N,N-dimethylformamide, at 45xc2x0 C. followed by reduction of the resultant oxobutanoate using hydrazine hydrate and potassium hydroxide in ethanol glycol at reflux temperature. Similarly the compound wherein X is 6-thiomethyl and Z is methylene can be prepared from the commercially available 6-methoxy analogue by the method described in Chem. Pharm. Bull., 1984, 32, 130.
Compounds wherein X is (C1-6)alkyloxy, wherein (C1-6)alkyloxy has the meaning as previously defined, can be prepared from the 6-methoxy analogue by treatment with hydrogen bromide in acetic acid followed by reaction of the resulting phenol with an appropriate alkyl halide, typically an alkyl bromide or alkyl iodide in dimethylformamide in the presence of a suitable acid scavenger such as potassium or cesium carbonate at elevated temperatures. Alternatively, the required ethers can be prepared by reaction of the phenol with an alcohol according to Mitsunobo""s conditions which are known to those skilled in the art.
Compounds wherein X is (C6-12)aryloxy, wherein (C6-12)aryloxy is defined as above, can be prepared from the aforementioned phenol using the methods described in Chem. Pharm.Bull. 1978, 26, 2475-2482. Said phenol derivatives can likewise be converted with triflic anhydride to the corresponding triflate derivative, the trifate group of which can be converted, using methods known to the skilled person, to an amino group.
Compounds of formula (VI) wherein Z is oxygen can be prepared as described in J.Chem.Soc., 1954, 4299-4303; those wherein Z is S can be synthesized as indicated in J.Am.Chem.Soc., 1954, 76, 5065-5069.
The skilled person will be aware of numerous general synthetic methods that allow the conversion of a certain group X in a compound according to one of the Formulas I-VI to another group X according to the definition of X. For example, a compound according to formula III; wherein X is a 6-bromo group, can be sequentially converted to a methoxycarbonyl group (X=COOR6, wherein R6 is methyl) and a cyano group.
The compounds of this invention possess at least two chiral carbon atoms, and can therefore be obtained as pure stereoisomers, or as a mixture of stereoisomers. Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, enantioselective enzymatic ester hydrolysis, crystallization of salts which are obtained from optically active acids and the racemic mixture, separation of stereoisomers or enantiomers using chromatography on chiral media, or on straight phase or reversed phase chromatography media. Such methods are for example described in Chirality in Industry (edited by A. N. Collins, G. N. Sheldrake and J. Crosby, 1992; John Wiley).
Pharmaceutically acceptable salts of the compounds of formula I may be obtained by treating the free base of the compounds according to formula I with a mineral acid such as dihydrochloric acid, phosphoric acid, sulphuric acid, preferably hydrochloric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulphonic acid and the like. Pharmaceutically acceptable salts of compounds of formula I wherein R1 is COOR7 and R7 is hydrogen, may be obtained by treating the acid or zwitterionic form of those compounds with an organic base or a mineral base, for example sodium, potassium or lithium hydroxide.
The compounds of the invention may be administered for humans in a dosage of 0.001-50 mg per kg body weight, preferably in a dosage of 0.01-20 mg per kg body weight.
The pharmaceutical compositions for use according to the invention comprise an aminomethylcarboxylic acid derivative having formula I or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The term xe2x80x9cacceptablexe2x80x9d means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. The compositions can be prepared in accordance with standard techniques such as for example are described in the standard reference, Gennaro et al., Remington""s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). Compositions include e.g. those suitable for oral, sublingual, intranasal, subcutaneous, intravenous, intramuscular, local, or rectal administration, and the like, all in unit dosage forms for administration.
For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, and suspensions.
For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.